EP1819698B1 - 1-[(6-substituiertes alkoxychinoxalinyl) aminocarbonyl]-4-(hetero)arylpiperazinderivate - Google Patents

1-[(6-substituiertes alkoxychinoxalinyl) aminocarbonyl]-4-(hetero)arylpiperazinderivate Download PDF

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EP1819698B1
EP1819698B1 EP05809031A EP05809031A EP1819698B1 EP 1819698 B1 EP1819698 B1 EP 1819698B1 EP 05809031 A EP05809031 A EP 05809031A EP 05809031 A EP05809031 A EP 05809031A EP 1819698 B1 EP1819698 B1 EP 1819698B1
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compound
piperazine
tumors
general formula
aminocarbonyl
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EP1819698A1 (de
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Young-Dae Gong
Moon-Kook Jeon
Dong-Su Kim
Jae Yang Kong
Gun-Do Kim
Chang-Ho Ahn
Young Bok Lee
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Korea Research Institute of Chemical Technology
Opus Genetics Inc
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Korea Research Institute of Chemical Technology
Rexahn Pharmaceuticals Inc
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Priority claimed from KR1020040094233A external-priority patent/KR100739233B1/ko
Priority claimed from KR1020040094232A external-priority patent/KR20060053788A/ko
Application filed by Korea Research Institute of Chemical Technology, Rexahn Pharmaceuticals Inc filed Critical Korea Research Institute of Chemical Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel quinoxaline-piperazine compounds, 1-[(6-substituted alkoxyquinoxalinyl)aminocarbonyl]-4-(hetero)arylpiperazine derivatives and pharmaceutically acceptable salt thereof, process for the preparation thereof, and therapeutic methods for the treatment of hyperproliferative disorders, including cancers, by administering quinoxaline-piperazine compounds.
  • Chemotherapeutics kill tumor cells by interfering with various stages of the cell division process.
  • chemotherapeutics include alkylating agents (e.g., cyclophosphamide, carmustine, cisplatin), antimetabolites (e.g., methotrexate, 5-FU, gemcitabine), cytotoxic antibiotics (e.g., doxorubicin, mitomycin) and plant derivatives (e.g., paclitaxel, vincristine, etoposide).
  • alkylating agents e.g., cyclophosphamide, carmustine, cisplatin
  • antimetabolites e.g., methotrexate, 5-FU, gemcitabine
  • cytotoxic antibiotics e.g., doxorubicin, mitomycin
  • plant derivatives e.g., paclitaxel, vincristine, etoposide.
  • C hemotherapy is used as a primary treatment for leukemias
  • Novel piperazine compounds may provide potent new therapeutic molecules for the treatment of disorders such as tumors.
  • the compounds listed in U. S. Patent Application Publication No. 2003/0092910 has no other group except hydrogen at C-6 of quinoxaline ring of 1-[(2-alkoxyquinoxalin-3-yl)aminocarbonyl-4-arylpiperazine and the compounds with other groups except hydrogen at C-6 of quinoxaline have not been prepared and tested as an antitumor agent.
  • the present invention has studied 1-[(2-alkoxyquinoxalin-3-yl)aminocarbonyl-4-arylpiperazine derivatives because of its prominent antitumor activities with very low toxicities and presents novel 1-[(6-substituted alkoxyquinoxalinyl)aminocarbonyl]-4-(hetero)arylpiperazine derivatives with other functional groups except hydrogen at C-6 of quinoxaline ring of 1-[(2-alkoxyquinoxalin-3-yl)aminocarbonyl-4-arylpiperazine derivatives, the process of preparation and strong antitumor activities of these new compounds.
  • one object of the present invention is to provide the novel compounds, 1-[(6-substituted alkoxyquinoxalinyl)aminocarbonyl]-4-(hetero)arylpiperazine derivatives.
  • Another object of the present invention is to provide a process for the preparation of the novel compounds, 1-[(6-substituted alkoxyquinoxalinyl)aminocarbonyl]-4-(hetero)arylpiperazine derivatives.
  • a further object of the present invention is to use 1-[(6-substituted alkoxyquinoxalin-yl)aminocarbonyl]-4-(hetero)arylpiperazine derivatives as antitumor agent.
  • the present invention comprises a novel quinoxalin-piperazine derivative of the general formula (1) or its pharmaceutically acceptable salt, process for the preparation thereof and their use in the treatment of a hyperproliferative disorder, disease or condition in a a subject (e.g. , a human patient or other animal subject).
  • Methods disclosed comprise administering to a subject an effective amount of a quinoxalin-piperaine compound according to the invention.
  • a treatment can, e.g. , prevent, ameliorate, and/or inhibit symptoms of the hyperproliferative condition, and/or can prevent or inhibit cellular proliferation or growth, for instance in a tumor, such as a malignant neoplasm.
  • a treatment strategy of the invention would decrease the tumor burden, at least to a measurable degree, and improve survival of patients suffering from the hyperproliferative condition.
  • diseases, disorders and conditions susceptible to treatment by agents of the invention are neoplasms, and more specifically tumors of various origins (lung, colon, stomach, smooth muscle, esophagus, non-Hodgkin's lymphoma, non-small cell lung cancer, etc.).
  • Compounds useful in methods of the invention include quinoxaline-piperazine derivatives having formula (1), 1-[(6-substituted alkoxyquinoxalinyl)aminocarbonyl] -4-(hetero)arylpiperazine derivatives:
  • X and Y are independently N or C-R 7 ;
  • R 1 is C 1 -C 6 alkoxy, C 1 -C 6 alkyl or halogen;
  • R 3 is C 1 -C 6 alkyl;
  • R 4 , R 5 , R 6 and R 7 are independently hydrogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylcarbonyl, halogen, cyano or nitro.
  • 'halogen' represents F, Cl, Br or I.
  • alkoxy' represents C 1 -C 6 alkoxy containing methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and t- butoxy.
  • alkyl' represents C 1 -C 6 alkyl containing methyl, ethyl, propyl, isopropyl, n- butyl, isobutyl, t- butyl, n- pentyl, isopentyl, n- hexyl, isohexyl and cyclohexyl.
  • 'haloalkyl' represnets C 1 -C 6 alkyl, for example trifluoromethyl, in which hydrogen was exchanged with halogen such as F or Cl.
  • alkylcarbonyl' represents carbonyl ketonized with alkyl such as methylcarbonyl or ethylcarbonyl.
  • X and Y are independently N, C-H, C-F, C-Cl, C-CN, C-CH 3 , or C-OCH 3
  • R 1 is F, Cl, methyl or methoxy
  • R 3 is methyl
  • R 4 , R 5 , and R 6 are independently hydrogen, Cl, Br, nitro, methyl, trifluoromethyl, methoxy or acetyl
  • R 7 is hydrogen, F, Cl, cyano, methyl or methoxy.
  • This invention also presents a process for the preparation of the compounds of general formula (1).
  • the preparation method of formula (1) comprises a two-step procedure as shown in the following scheme 1.
  • the two-step reaction in scheme 1 may be carried out successively without purification of the compound of the general formula (3) which is an intermediate produced in the above process.
  • the reaction may be carried out in a conventional organic solvent such as, for example, tetrahydrofuran (THF), dichloromethane, acetonitrile, chloroform and dimethylformamide.
  • a conventional organic solvent such as, for example, tetrahydrofuran (THF), dichloromethane, acetonitrile, chloroform and dimethylformamide.
  • reaction is preferably carried out in the presence of a coupling agent such as a conventional inorganic or organic base.
  • a coupling agent such as a conventional inorganic or organic base.
  • conventional inorganic or organic bases used in the reaction may include sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine and 1,8-diazabicyclo[5.4.0]undec-7-ene (hereinafter DBU).
  • the reaction may be carried out at a temperature between 0 °C and boiling point of the solvent used, preferably at room temperature to 100 °C and for 5-48 hours, preferably for 10-24 hours.
  • reaction of the compound (3) with the compound (4) to give the compound (1) may be carried out in the presence of a conventional organic solvent at the temperature of 50-100 °C for 5-48 hours.
  • the compound (4) may be used by 1.0-1.5 equivalent.
  • reaction is preferably carried out in the presence of a conventional inorganic or organic base, such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, DBU or the like.
  • a conventional inorganic or organic base such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, DBU or the like.
  • the compounds of the general formula (2) that are used as the starting material, 6-substituted-2-alkoxy-3-aminoquinoxaline, are novel compounds and may be prepared by the following scheme 2; reacting a compound of the general formula (5) with sodium alkoxide which is NaOR 3 (R 3 is C 1 -C 6 alkyl) to give a compound of the general formula (2); wherein R 1 , and R 3 are the same as defined in scheme 1.
  • the compound of the general formula (5) may be prepared by a known method described in, for example, J. Med Chem., 1995, 38, 3720-3740 or Bull. Chem. Soc. Jpn., 1998, 71, 1125-1135 .
  • the alkoxy reaction in scheme 2 may be carried out with sodium alkoxide in a conventional organic solvent such as THF and sodium alkoxide may be used in an amount of 1.0-10.0 equivalents, preferably 1.0-1.1 equivalents with reference to the starting compound, the compound of the general formula (5).
  • a compound of the general formula (2) may be prepared by the following scheme 3; reacting a compound of the general formula (6) with 2,4-dimethoxybenzylamine to give a compound of the general formula (7) and reacting the compound of the formula (7) with trifluoroacetic acid (TFA) to give a compound of the general formula (2); wherein R 1 , and R 3 are the same as defined in scheme 1.
  • TFA trifluoroacetic acid
  • the compound of the general formula (6) may be prepared by a known method described in, for example, J. Med. Chem. 1990, 33, 2240-2254 .
  • reaction of the compound of the general, formula (6) with 2,4-dimethoxybenzylamine in scheme 2 may be carried out in a conventional organic solvent such as dimethylsulfoxide to produce a compound of the general formula (7); and 2,4-dimethoxybenzylamine may be used in an amount of 1.0-5.0 equivalents, preferably 1.0-1.1 equivalents with reference to the compound of the general formula (6).
  • Trifluoroacetic acid may be used in an amount of 0.5-1.5 equivalents, preferably 1.0 equivalent with reference to dichloromethane.
  • Compounds of the pesent invention can be very active against a wide range of hyperproliferatvie diseases, including tumors and used as an anti-tumor agent.
  • the compounds of the present invention can be also mixed with pharmaceutically acceptable vehicles by a known method to give pharmaceutical compositions and thus the pharmaceutical compositions can be used to prevent or treat various kinds of tumors of human beings or mammals.
  • the present invention includes pharmaceutical compositions containing a compound of the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Pharmaceutically acceptable salts of compounds of the general formula (1) are pharmaceutically acceptable inorganic, organic acids, alkali metal and ammonium; for example, salts with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogensulfate, phosphoric acid, nitric acid, carbonic acid; salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, fumaric acid, lactobionic acid, salicylic acid, acetyl salicylic acid(aspirin); salts with amino acids such as glycine, alanine, valine, leucine, isoleucine, serine, cysteine, cystine, asparaginic acid, glutamic acid, lysine, arginine, tyrosine, proline; salts with sulfonic
  • the novel compounds of the general formula (1) and pharmaceutically acceptable salts thereof may be combined with a non-toxic pharmaceutically acceptable vehicle such as carrier, adjuvant, and expient and then the mixture may be administered orally or parenterally in the form of tablets, capsules, troches, solutions, suspensions to prevent or treat various kinds of tumors of human beings or mammals.
  • a non-toxic pharmaceutically acceptable vehicle such as carrier, adjuvant, and expient
  • Vehicles which can be used in the preparation of pharmaceutical compositions containing the compound of the general formula (1) as the active ingredient may include a sweetening agent, a binding agent, a dissolving agent, aids for dissolution, a wetting agent, an emulsifying agent, an isotonic agent, an adsorbent, a degrading agent, an antioxidant, an antiseptics, a lubricating agent, a filler, perfume or the like; such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, calcium stearate, magnesium aluminum silicate, starch, gelatine, tragacanth gum, glycine, silica, alginic acid, sodium alginate, methyl cellulose, sodium carboxy methyl cellulose, agar, water, ethanol, polyethylenglycol, polyviny
  • Daily dosage of the compound of the general formula (1) may be varied depending on age, body weight, sex of a patient, type of administration, health condition, degree of disease, etc. and generally 0.01 mg to 5,000 mg per day for 70 kg adult may be administered one to several times according to a doctor's prescription or a pharmacist's indication.
  • compositions containing the compound of formula (1), or a pharmaceutically acceptable salt thereof (hereafter compound X) for therapeutic or prophylactic use in humans.
  • the formulations may be obtained by conventional procedures well known in the pharmaceutical art and are not limited to the representative pharmaceutical dosage forms.
  • Cancer cells used in this study to determine the effect of quinazoline compounds were obtained from the following sources: Human OVCAR-3 (ovary), MCF-7 (breast, hormone-dependent), MDA-MB-231 (breast), PC3 (prostate), HepG2 (liver), A549 (lung), Caki-1 (kidney), HT-29 (colon), HCT116 (colon) and PANC-1 (pancreas) from the American Type Culture Collection (ATCC) (Manassas, VA); MKN-45 (stomach) from DSMZ (Germany); UMRC2 (kidney) from the U. S.
  • ATCC American Type Culture Collection
  • VA Manassas, VA
  • MKN-45 stomach
  • DSMZ Germany
  • UMRC2 kidney
  • OVCAR-3, MCF-7, PC3, HepG2, A549, HT-29 and MKN-45 were grown in RPMI1640 medium (Invitrogen, Carlsbad, CA) supplemented with 10 % fetal bovine serum ('FBS'), 1 mM sodium pyruvate, 10 mM HEPES and 100 U/ml penicillin and 100 m g/ml streptomycin ('P/S').
  • MDA-MB-231, HCT116, UMRC2, Caki-1, PANC-1 and HEK293 cells were maintained in Dulbecco'smodified Eagle's medium ('DMEM', Invitrogen) supplemented with 10 % FBS, P/S, 10 mM HEPES and 2 mM L-glutamine.
  • HUVEC was maintained in M 199 supplemented with basic fibroblast growth factor ('bFGF) 3 mg/ml, Heparn 100 mg/ml and FBS 20 %. All cells were incubated at 37 °C under humidified 5 % CO 2 .
  • the growth inhibition of the substituted quinoxalin-piperazine compounds against a variety of human tumor cells was evaluated.
  • the relative importance of particular substituent groups on the compounds was also studied.
  • the substituted piperazinee derivative compounds, prepared as described above, were tested, along with DMSO as a control.
  • the growth inhibition assay of various compounds against human tumor cell lines was performed using the Sulforhodamine B ('SRB') method (Skehan et al., J. National Cancer Institute, 1990, 82 , 1107-1112). Briefly, exponentially growing tumor cells were seeded into a 96-well plate at a density of 2 ⁇ 3 x 10 3 cells/well and treated with quinazoline compounds the next day. Triplicate wells were used for each treatment. The cells were incubated with the various compounds for 96 hours at 37 °C in a humidified 5 % CO 2 atmosphere.
  • % S ⁇ u ⁇ r ⁇ v ⁇ i ⁇ v ⁇ a ⁇ l l ⁇ i ⁇ v ⁇ e c ⁇ e ⁇ l ⁇ l n ⁇ u ⁇ m ⁇ b ⁇ e ⁇ r t ⁇ e ⁇ s ⁇ t / l ⁇ i ⁇ v ⁇ e c ⁇ e ⁇ l ⁇ l n u ⁇ m ⁇ b ⁇ e ⁇ r c ⁇ o ⁇ n ⁇ t ⁇ r ⁇ o l ⁇ 100
  • the IC 50 values were calculated by non-linear regression analysis.
  • novel compounds of the present invention may provided novel quinoxaline-piperazine derivatives or pharmaceutically acceptable salts thereof which have the strong anti-proliferative effect and are useful for treating hyperproliferative disorders, including cancers, by administering quinoxaline-piperazine compounds.

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Claims (16)

  1. Verbindung mit der allgemeinen Formel (1) und die pharmazeutisch verträglichen
    Salze davon,
    Figure imgb0016
     wobei X und Y unabhängig N oder C-R7 sind; R1 C1-C6-Alkoxy, C1-C6-Alkyl oder Halogen ist; R3 C1-C6-Alkyl ist; R4, R5, R6 und R7 unabhängig Wasserstoff, C1-C6-Alkoxy, C1-C6-Alkyl, C1-C6-Haloalkyl, C1-C6-Alkylearbonyl, Halogen, Cyano oder Nitro sind.
  2. Verbindung mit der Formel (1) nach Anspruch 1, wobei X und Y unabhängig N, C-H, C-F, C-Cl, C-CN, C-CH3 oder C-OCH3 sind.
  3. Verbindung mit der Formel (1) nach Anspruch 1, wobei R1 F, Cl, Methyl oder Methoxy ist.
  4. Verbindung mit der Formel (1) nach Anspruch 1, wobei R3 Methyl ist.
  5. Verbindung mit der Formel (1) nach Anspruch 1, wobei R4, R5 und R6 unabhängig Wasserstoff, Cl, Br, Nitro, Methyl, Trifluormethyl, Methoxy oder Acetyl sind.
  6. Verbindung mit der Formel (1) nach Anspruch 1, wobei R7 Wasserstoff, F, Cl, Cyano, Methyl oder Methoxy ist.
  7. Verfahren für die Herstellung einer Verbindung mit der allgemeinen Formel (1) oder eines pharmazeutisch verträglichen Säureadditionssalzes davon, umfassend Umsetzen einer 6-substituierten 2-Alkoxy-3-aminochinoxalin-Verbindung mit der allgemeinen Formel (2) mit einem eine L-C(=O)-L'-Gruppe bereitstellenden Mittel in einem herkömmlichen Lösungsmittel in Gegenwart einer Base, um eine Verbindung mit der allgemeinen Formel (3) zu erhalten, und anschließend Umsetzen der Verbindung mit der allgemeinen Formel (3) mit einer 1-(Hetero)arylpiperazin-Derivat-Verbindung mit der allgemeinen Formel (4) unter Gewinnung der Verbindung mit der allgemeinen Formel (1);
    Figure imgb0017
    Figure imgb0018
    Figure imgb0019
    Figure imgb0020
     wobei X, Y, R1, R3, R4, R5 und R6 dieselben wie in Anspruch 1 definiert sind und L und L' unabhängig Imidazol, Cl, Ethoxy, Phenoxy oder 4-Nitrophenoxy sind.
  8. Verfahren nach Anspruch 7 für die Herstellung einer 6-substituierten 2-Alkoxy-3-aminochinoxalin-Verbindung mit der allgemeinen Formel (2), umfassend Umsetzen einer Verbindung mit der allgemeinen Formel (5) mit Natriumalkoxid, das NaOR3 ist (R3 ist C1-C6-Alkyl), unter Gewinnung einer Verbindung mit der allgemeinen Formel (2);
    Figure imgb0021
     wobei R1 dasselbe wie in Anspruch 1 definiert ist.
  9. Verfahren nach Anspruch 7 für die Herstellung einer 6-substituierten 2-Alkoxy-3-aminochinoxalin-Verbindung mit der allgemeinen Formel (2), umfassend Umsetzen einer Verbindung mit der allgemeinen Formel (6) mit 2,4-Dimethoxybenzylamin unter Gewinnung einer Verbindung mit der allgemeinen Formel (7) und Umsetzen der Verbindung mit der Formel (7) mit Trifluoressigsäure (TFA) unter Gewinnung einer Verbindung mit der allgemeinen Formel (2);
    Figure imgb0022
    Figure imgb0023
     wobei R1 und R3 dieselben wie in Anspruch 1 definiert sind.
  10. Pharmazeutische Zusammensetzung, die eine 1 [(6-substituierte Alkoxychinoxalinyl)aminocarbonyl]-4-(hetero)arylpiperazin-Derivat-Verbindung mit der allgemeinen Formel (1) oder ein pharmazeutisch verträgliches Salz davon nach Anspruch 1 in Zusammenhang mit einem pharmazeutisch verträglichen Verdünnungsmittel oder Träger umfasst.
  11. Pharmazeutische Zusammensetzung nach Anspruch 10, wobei die Zusammensetzung für die Behandlung einer proliferativen Erkrankung verwendet wird.
  12. Pharmazeutische Zusammensetzung nach Anspruch 11, wobei die proliferative Erkrankung ein Tumor ist.
  13. Pharmazeutische Zusammensetzung nach Anspruch 12, wobei der Tumor irgendeiner ist, der aus der Gruppe ausgewählt ist, die aus Tumoren des Eierstocks, Tumoren der Brust, Gebärmutterhalstumoren, Tumoren der Prostata, Tumoren der Leber, Lungentumoren, Nierentumoren, Dickdarmtumoren, Bauchspeicheldrüsentumoren, Gehirntumoren, Magentumoren und Melanom besteht.
  14. Antiproliferatives Mittel mit der Verbindung der Formel (1) nach Anspruch 1 als Wirkstoff.
  15. Antiproliferatives Mittel nach Anspruch 14, wobei das antiproliferative Mittel ein Antitumormittel ist.
  16. Antiproliferatives Mittel nach Anspruch 14 oder 15, wobei das antiproliferative Mittel für die Behandlung von irgendeinem verwendet wird, das aus der Gruppe ausgewählt ist, die aus Tumoren des Eierstocks, Tumoren der Brust, Gebärmutterhalstumoren, Tumoren der Prostata, Tumoren der Leber, Lungentumoren, Nierentumoren, Dickdarmtumoren, Bauchspeicheldrüsentumoren, Gehirntumoren, Magentumoren und Melanom besteht.
EP05809031A 2004-11-17 2005-10-18 1-[(6-substituiertes alkoxychinoxalinyl) aminocarbonyl]-4-(hetero)arylpiperazinderivate Expired - Lifetime EP1819698B1 (de)

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PL05809031T PL1819698T3 (pl) 2004-11-17 2005-10-18 Pochodne 1-[(6-podstawione alkoksychinoksalinylo)aminokarbonylo]-4-(hetero)arylopiperazyny

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KR1020040094233A KR100739233B1 (ko) 2004-11-17 2004-11-17 1-[(3-알콕시-6-치환-퀴녹살린-2-일)아미노카르보닐]-4-(헤테로)아릴피페라진 유도체
KR1020040094232A KR20060053788A (ko) 2004-11-17 2004-11-17 1-[(2-알콕시-6-치환-퀴녹살린-3-일)아미노카르보닐]-4-(헤테로)아릴피페라진 유도체
PCT/KR2005/003463 WO2006054830A1 (en) 2004-11-17 2005-10-18 1-[(6,7-substituted alkoxyquinoxalinyl)aminocarbonyl]-4-(hetero)arylpiperazine derivatives

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EP1819698B1 true EP1819698B1 (de) 2011-02-23

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US (2) US8314100B2 (de)
EP (1) EP1819698B1 (de)
JP (1) JP6097946B2 (de)
CN (1) CN103524436B (de)
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AU (1) AU2005307209B2 (de)
BR (1) BRPI0517734A (de)
CA (1) CA2587891C (de)
DE (1) DE602005026557D1 (de)
MX (1) MX2007005863A (de)
PL (1) PL1819698T3 (de)
WO (1) WO2006054830A1 (de)

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JP6097946B2 (ja) 2004-11-17 2017-03-22 レクサン ファーマシューティカルズ インコーポレイテッド １−［（６，７−置換−アルコキシキノキサリニル）アミノカルボニル］−４−（ヘテロ）アリールピペラジン誘導体
KR101140133B1 (ko) 2010-02-17 2012-05-02 한국화학연구원 1-(6,7-다이플루오르-3-메톡시퀴녹살린-2-일)-3-［1-(헤테로아릴메틸)피페리딘-4-일］ 우레아 유도체, 그 제조방법 및 그의 용도
US9744167B2 (en) 2013-06-28 2017-08-29 Rexahn Pharmaceuticals, Inc. Nanoparticulate compositions and formulations of piperazine compounds
KR101727412B1 (ko) * 2014-12-08 2017-04-17 동국대학교 산학협력단 신규한 4-(아릴)-N-(2-알콕시티에노[3,2-b]피라진-3-일)-피페라진-1-카복스아미드 유도체 및 이의 항증식 효과
JP2018526392A (ja) 2015-09-04 2018-09-13 レクサン ファーマシューティカルズ インコーポレイテッド キノキサリニル−ピペラジンアミドの使用方法
WO2017213452A1 (ko) * 2016-06-09 2017-12-14 동국대학교 산학협력단 신규한 4-(아릴)-n-(3-알콕시퓨로[2,3-b]피라진-2-일)-피페라진-1-카복스아미드 유도체 및 이의 항증식 효과
KR101872645B1 (ko) 2016-06-09 2018-08-03 동국대학교 산학협력단 신규한 4-(아릴)-N-(3-알콕시퓨로[2,3-b]피라진-2-일)-피페라진-1-카복스아미드 유도체 및 이의 항증식 효과

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SE441449B (sv) * 1979-02-09 1985-10-07 Roussel Uclaf Heterocykliska derivat och farmaceutiska kompositioner innehallande dessa derivat
FR2448541A1 (fr) 1979-02-09 1980-09-05 Roussel Uclaf Nouveaux derives de l'oxoimidazoquinoxaline et leurs sels, leur procede de preparation, leur application comme medicaments et les compositions pharmaceutiques les renfermant
US6071697A (en) * 1992-08-03 2000-06-06 Max-Planck Gesellschaft Zur Forderung Der Wissenschaften E.V. Method for testing the differentiation status in pancreatic cells of a mammal
EP0850222B1 (de) 1996-06-29 2003-05-28 Samjin Pharmaceutical Co., Ltd. Piperazin-derivate und verfahren zu ihrer herstellung
WO2000052001A1 (en) * 1999-03-03 2000-09-08 Samjin Pharmaceutical Co., Ltd. Piperazine derivatives and process for the preparation thereof
AU2001264376A1 (en) * 2000-06-15 2001-12-24 Chaconne Nsi Co., Ltd. Urea derivative useful as an anti-cancer agent and process for preparing same
AR043059A1 (es) 2002-11-12 2005-07-13 Bayer Pharmaceuticals Corp Derivados de indolil pirazinona utiles para el tratamiento de trastornos hiper-proliferativos
RU2005135337A (ru) 2003-04-16 2006-06-10 Астразенека Аб (Se) Производные хиназолина для лечения злокачественного новообразования
JP6097946B2 (ja) 2004-11-17 2017-03-22 レクサン ファーマシューティカルズ インコーポレイテッド １−［（６，７−置換−アルコキシキノキサリニル）アミノカルボニル］−４−（ヘテロ）アリールピペラジン誘導体

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DE602005026557D1 (de) 2011-04-07
AU2005307209B2 (en) 2009-11-19
US8314100B2 (en) 2012-11-20
ATE499366T1 (de) 2011-03-15
US20130053390A1 (en) 2013-02-28
JP2008520653A (ja) 2008-06-19
CN103524436B (zh) 2015-09-23
US8598173B2 (en) 2013-12-03
WO2006054830A1 (en) 2006-05-26
US20080318963A1 (en) 2008-12-25
AU2005307209A1 (en) 2006-05-26
MX2007005863A (es) 2007-10-19
CA2587891A1 (en) 2006-05-26
CN103524436A (zh) 2014-01-22
CA2587891C (en) 2010-08-31
PL1819698T3 (pl) 2011-08-31
JP6097946B2 (ja) 2017-03-22
BRPI0517734A (pt) 2008-10-21
EP1819698A1 (de) 2007-08-22

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